Propynyl or dienyl biaromatic compounds

ABSTRACT

The invention relates to novel propynyl or dienyl biaromatic compounds which have the general formula (I)as well as to the use of these compounds in pharmaceutical compositions intended for use in human or veterinary medicine (dermatological, rheumatic, respiratory, cardiovascular and ophthalmological complaints in particular), or alternatively in cosmetic compositions.

This application is a divisional of application Ser. No. 08/952,302,filed Jan. 26, 1998, now U.S. Pat. No. 6,046,220, which is a 371 ofPCT/FR97/00390, filed Mar. 5, 1997.

The invention relates to propynyl or dienyl biaromatic compounds asnovel and useful industrial products. It also relates to the use ofthese novel compounds in pharmaceutical compositions intended for use inhuman or veterinary medicine, or alternatively in cosmetic compositions.

The compounds according to the invention have pronounced activity in thefields of cell differentiation and cell proliferation, and findapplications more particularly in the topical and systemic treatment ofdermatological complaints associated with a disorder of keratinization,dermatological (or other) complaints with an inflammatory and/orimmunoallergic component, and dermal or epidermal proliferations, thesebeing either benign or malignant. These compounds may also be used inthe treatment of degenerative diseases of connective tissue, forcombating either light-induced or chronological ageing of the skin, andfor treating disorders of cicatrization. They moreover find anapplication in the ophthalmological field, in particular in thetreatment of corneopathies.

The compounds according to the invention may also be used in cosmeticcompositions for body and hair hygiene.

The compounds according to the invention may be represented by thegeneral formula (I) below:

in which:

R₁ represents

(i) the —CH₃ radical

(ii) the radical —CH₂—O—R₆

(iii) the radical —O—R₆

(iv) the radical —CO—R₇

R₆ and R₇ having the meanings given below,

Ar represents a radical chosen from the radicals of formulae (a)-(e)below:

 R₅ and R₆ having the meanings given below,

X represents a radical of formula:

 R₈ R₉ having the meanings given below,

R₂ and R₃, which may be identical or different, represent

(i) a hydrogen atom,

(ii) a linear or branched alkyl radical having from 1 to 20 carbonatoms,

(iii) a radical —OR₆,

(iv) a radical —SR₆,

R₆ having the meaning given below,

it being understood that R₂ and R₃, taken together, may form, with theadjacent aromatic ring, a 5- or 6-membered ring optionally substitutedwith methyl groups and/or optionally interrupted by an oxygen or sulphuratom,

and it being understood that R₂ and R₃ cannot simultaneously have themeanings (i), (iii) and (iv) mentioned above,

R₄ and R₅, which may be identical or different, represent a hydrogenatom, a halogen atom, a linear or branched alkyl radical having from 1to 20 carbon atoms or a radical —OR₆,

it being understood that when R₄ is a hydroxyl radical, then R₂ and R₃form, with the adjacent aromatic ring, a 5- or 6-membered ringoptionally substituted with methyl groups and/or optionally interruptedby an oxygen or sulphur atom,

R₆ represents a hydrogen atom, a lower alkyl radical or a radical —COR₁₀

R₁₀ having the meaning given below,

R₇ represents:

(a) a hydrogen atom

(b) a lower alkyl radical

(c) a radical of formula:

 R′ and R″ having the meaning given below,

(d) a radical —OR₁₁,

(e) a radical —NHOR₆,

R₁₁ having the meaning given below,

R₈ and R₉, taken separately, either simultaneously have the samemeaning: a hydrogen atom or a radical —OR₁₀, or one of them represents ahydrogen atom and the other represents a lower alkyl radical, or, takentogether, form a ring —Y—(CH₂)_(n)—Y—, with Y representing an oxygen orsulphur atom and with n equal to 2 or 3,

R₁₀ represents a lower alkyl radical,

R₁₁ represents a hydrogen atom, a linear or branched alkyl radicalhaving from 1 to 20 carbon atoms, an alkenyl radical, a mono- orpolyhydroxyalkyl radical, an optionally substituted aryl or aralkylradical, a sugar residue or an amino acid or peptide residue,

R′ and R″, which may be identical or different, represent a hydrogenatom, a lower alkyl radical, a mono- or polyhydroxyalkyl radical, anoptionally substituted aryl radical or an amino acid or sugar residue,or alternatively, taken together, form a heterocycle.

The invention is also directed towards compounds which are intermediatesin the synthesis of the compounds of general formula (I), of generalformula (II)

in which R₁ and Ar have the same meanings as for the general formula (I)and R′₂ and R′₄, which may be identical or different, represent a linearor branched alkyl radical having from 1 to 20 carbon atoms.

The invention is also directed towards the salts of the compounds offormulae (I) and (II) when R₁ represents a carboxylic acid function, andthe geometrical and optical isomers of the said compounds of formulae(I) and (II).

When the compounds according to the invention are in the form of salts,they are preferably salts of an alkali metal or alkaline earth metal, oralternatively of zinc or of an organic amine.

According to the present invention, the expression lower alkyl radicalis understood to refer to a radical having from 1 to 12, preferably from1 to 9, carbon atoms, advantageously the methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, pentyl, hexyl, heptyl, nonyl, decyl anddodecyl radicals.

The expression linear alkyl radical having from 1 to 20 carbon atoms isunderstood to refer in particular to the methyl, ethyl, propyl, pentyl,hexyl, octyl, decyl, dodecyl, hexadecyl and octadecyl radicals.

The expression branched alkyl radical having from 1 to 20 carbon atomsis understood to refer in particular to the 2-ethylhexyl, 2-methylbutyl,2-methylpentyl, 1-methylhexyl and 3-methylheptyl radicals.

Among the monohydroxyalkyl radicals, a radical having 2 or 3 carbonatoms, in particular a 2-hydroxyethyl, 2-hydroxypropyl or3-hydroxypropyl radical, is preferred.

Among the polyhydroxyalkyl radicals, a radical having from 3 to 6 carbonatoms and from 2 to 5 hydroxyl groups, such as the 2,3-dihydroxypropyl,2,3,4-trihydroxybutyl and 2,3,4,5-tetrahydroxypentyl radicals or thepentaerythritol residue, is preferred.

Among the aryl radicals, a phenyl radical optionally substituted with atleast one halogen atom, a hydroxyl or a nitro function, is preferred.

Among the aralkyl radicals, the benzyl or phenethyl radical optionallysubstituted with at least one halogen atom, a hydroxyl or a nitrofunction, is preferred.

Among the alkenyl radicals, a radical containing from 2 to 5 carbonatoms and having one or more ethylenic unsaturations, in particular suchas the allyl radical, is preferred.

The term sugar residue is understood to refer to a residue derived inparticular from glucose, galactose or mannose, or alternatively fromglucuronic acid.

The term amino acid residue is understood to refer in particular to aresidue derived from lysine, glycine or aspartic acid, and the termpeptide residue is understood to refer more particularly to a dipeptideor tripeptide residue resulting from the combination of amino acids.

Lastly, the term heterocycle is understood to refer preferably to apiperidino, morpholino, pyrrolidino or piperazino radical, optionallysubstituted in position 4 with a C₁-C₆ alkyl or mono- orpolyhydroxyalkyl radical as defined above.

When the radicals R₄ and R₅ represent a halogen atom, this is preferablya fluorine, bromine or chlorine atom.

Among the compounds of formula (I) above which fall within the scope ofthe present invention, mention may be made in particular of thefollowing compounds:

4-[3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-1-propynyl]benzoic acid.

2-Hydroxy-4-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-propynyl]benzoicacid.

4-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid.

Methyl2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate.

2-Hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid.

2-Hydroxy-4-[3-(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid.

2-Hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzenemethanol.

Diethanolamine2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate.

Lithium2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate.

4-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-propynyl]benzoicacid.

2-Hydroxy-4-[3-(4,4-dimethylthiochroman-6-yl)-1-propynyl]benzoic acid.

2-Hydroxy-4-[3-(8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoicacid.

2-Hydroxy-4-[3-(5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoicacid.

Ethyl4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate.

4-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamide.

N-Ethyl-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamide.

4-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid morpholide.

N-(4-Hydroxyphenyl)-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamide.

4-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzaldehyde.

4-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]phenol.

[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzenemethanol.

4-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]toluene.

Hexyl4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate.

N-Hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamide.

N-Hydroxy-2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benazamide.

2-Methyl-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid.

3-Methyl-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid.

6-[3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)propa-1,2-dienyl]nicotinicacid.

4-[3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)propa-1,2-dienyl]benzoicacid.

2-Hydroxy-4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)propa-1,2-dienyl]benzoicacid.

2-Hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-butynyl]benzoicacid.

5-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]-2-pyridinecarboxylicacid.

4-[3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoicacid.

2-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]-4-thiophenecarboxylicacid.

2-[3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]-4-thiophenecarboxylicacid.

2-Hydroxy-4-[3-(3-tert-butyl-4-methoxyphenyl)-1-propynyl]benzoic acid.

2-Hydroxy-4-[3-(3-tert-butyl-4-hydroxyphenyl)-1-propynyl]benzoic acid.

Among the compounds of formula (II) above which fall within the scope ofthe present invention, mention may be made in particular of thefollowing compounds:

4-[3-(3,5-Di-tert-butyl-4-oxo-2,5-cyclohexadien-1-ylidene)-1-propynyl]benzoicacid.

2-Hydroxy-4-[3-(3,5-Di-tert-butyl-4-oxo-2,5-cyclohexadien-1-ylidene)-1-propynyl]benzoicacid.

According to the present invention, the compounds of formula (I) or (II)more particularly preferred are those for which at least one, andpreferably all, of the following conditions is/are satisfied:

—R₁ represents the radical —CO—R₇,

Ar represents the radicals of formula (a) or (e).

More particularly, the preferred compounds of formula (I) are those forwhich R₈ and R₉, taken separately, either represent hydrogen atoms orone of them represents a hydrogen atom and the other represents a loweralkyl radical. Even more preferably, R₈ and R₉ represent hydrogen atoms.

The subject of the present invention is also processes for thepreparation of the compounds of formulae (I) and (II) above according tothe reaction schemes given in FIGS. 1, 2 and 3.

Thus, the derivatives of formula (Ia) may be prepared (FIG. 1) by areaction sequence comprising the action of a benzoyl chloride of formula(1) with an acetylenic derivative of formula (2) in the presence of aLewis acid (for example AlCl₃) in a chlorinated solvent, such asdichloromethane. The ketone (3) thus obtained is reduced to alcohol (4)by the action of an alkali metal hydride, such as sodium borohydride, inan alcoholic solvent (for example methanol). Reduction of the alcoholfunction to carbide may be carried out in the presence of trimethylsilyliodide in a solvent such as hexane or by hydride transfer from a silane,such as triethylsilane, in the presence of BF₃.Et₂O in a chlorinatedsolvent such as methylene chloride.

The derivatives of formula (Ia) may also be prepared (FIG. 1) by areaction sequence comprising the action of a benzoyl chloride of formula(1) with lithium trimethylacetylenide in the presence of a Lewis acid(for example AlCl₃) in a chlorinated solvent such as dichloromethane.The ketone (5) thus obtained is first reduced to alcohol (6) by theaction of an alkali metal hydride, such as sodium borohydride, in analcoholic solvent (for example methanol), and then to carbide (7), forexample by hydride transfer from a silane such as triethylsilane, in thepresence of BF₃.Et₂O in a chlorinated solvent such as methylenechloride. Next, the compound (7) is coupled with a halogenatedderivative (8) preferably an iodo or bromo derivative, in the presenceof a palladium catalyst [for examplebis(triphenylphosphine)palladium(II) chloride] in a solvent such astriethylamine.

The compounds of formula (Ib) may be obtained (FIG. 1) from the ketonederivative (3) by reaction with a glycol (ethylene glycol or propyleneglycol) or a dithiol (ethanedithiol, propanedithiol) in the presence ofpyridinium para-toluenesulphonate in an aromatic solvent such astoluene, with azeotropic entrainment of the water formed.

The compounds of formula (Ia) may also be prepared (FIG. 2) by areaction sequence comprising the action of lithiumtrimethylsilylacetylenide with the aldehyde compounds (9) anddeprotection with tetrabutylammonium fluoride in THF and production ofthe propargyl alcohol (6). Next, coupling is carried out with a haloderivative (8), preferably an iodo or bromo derivative, in the presenceof a palladium catalyst [for examplebis(triphenylphosphine)palladium(II) chloride] in a solvent such astriethylamine, and reduction of the alcohol function to carbide, asabove.

The compounds of formula (Ic) may be prepared (FIG. 2) from propargylalcohol derivatives (15) by reduction of the alcohol function to carbideas above, the propargyl alcohol derivatives (15) being prepared:

either by the action of a boron acetylenide (12) (prepared in situ fromlithium phenylacetylenide (11) and boron trifluoride at −78° C. in THF)with a tertiary benzamide of formula (13) in an organic solvent, such asTHF,

or by the action of lithium phenylacetylenide (11) on the aldehydederivatives (14).

The compounds of formula (Ic) may be prepared (FIG. 3) from thecompounds of formula (II) by the action of an alkali metal hydride, suchas sodium borohydride, in an alcoholic solvent (for example methanol).The compounds of formula (II) are prepared by a sequence of reactionsfrom hydroxybenzaldehyde compounds (16), comprising protection of thephenol function by the action of 2-(trimethylsilyl)ethoxymethyl chloride(SEMCl) (17), followed by the action of lithiumtrimethylsilylacetylenide (18) and selective deprotection of thetrimethylsilyl group borne by the acetylenic derivative withtetrabutylammonium fluoride in THF and production of the propargylalcohol (19). By coupling with a halo derivative (8), preferably an iodoor bromo derivative, in the presence of a palladium catalyst [forexample bis(triphenylphosphine)palladium(II) chloride] in a solvent,such as triethylamine, the compound (20) is obtained. Cleavage of theprotecting group (SEM) is carried out with trifluoroacetic acid in achlorinated solvent, such as methylene chloride.

The subject of the present invention is also, as medicinal product, thecompounds of formulae (I) and (II) as defined above.

These compounds are active in the test of differentiation of mouseembryonic teratocarcinoma cells (F9) (Cancer Research 43, p. 5258, 1983)and/or in the test of inhibition of ornithine decarboxylase afterinduction with TPA in mice (Cancer Research 38, pp. 793-801, 1978).These tests show the activities of the compounds in the fields of celldifferentiation and cell proliferation respectively.

These compounds also have very advantageous kinetic parameters for thepharmaceutical field when compared with other synthetic compounds ofretinoid type (the half-life for removal and the average residence timeof these compounds in the body are low).

The compounds of formula (I) or (II) according to the invention areparticularly suitable in the following fields of treatment:

1) for treating dermatological complaints associated with akeratinization disorder which has a bearing on differentiation and onproliferation, in particular for treating common acne, comedones,polymorphonuclear leukocytes, acne rosacea, nodulocystic acne, acneconglobata, senile acne and secondary acnes such as solar,medication-related or occupational acne,

2) for treating other types of keratinization disorder, in particularichthyosis, ichthyosiform states, Darier's disease, palmoplantarkeratoderma, leucoplasias and leucoplasiform states, and cutaneous ormucous (buccal) lichen,

3) for treating other dermatological complaints associated with akeratinization disorder with an inflammatory and/or immunoallergiccomponent and, in particular, all forms of psoriasis, whether it iscutaneous, mucous or ungual psoriasis and even psoriatic rheumatism, oralternatively cutaneous atopy, such as eczema or respiratory atopy oralternatively gingival hypertrophy; the compounds may also be used incertain inflammatory complaints which do not exhibit a disorder ofkeratinization,

4) for treating all dermal or epidermal proliferations, whether benignor malignant and whether they are of viral origin or otherwise, such ascommon warts, flat warts and verruciform epidermodysplasia, it beingalso possible for the oral or florid papillomatoses and theproliferations to be induced by ultraviolet radiation, in particular inthe case of basocellular and spinocellular epithelioma,

5) for treating other dermatological disorders such as bullosis andcollagen diseases,

6) for treating certain ophthalmological disorders, in particularcorneopathies,

7) for repairing or combating ageing of the skin, whether this islight-induced or chronological ageing, or for reducing actinic keratosesand pigmentations, or any pathologies associated with chronological oractinic ageing,

8) for preventing or curing the stigmata of epidermal and/or dermalatrophy induced by local or systemic corticosteroids, or any other formof cutaneous atrophy,

9) for preventing or treating cicatrization disorders or for preventingor repairing vibices,

10) for combating disorders of sebaceous functioning such as thehyperseborrhoea of acne or simple seborrhoea,

11) in the treatment or prevention of cancerous or precancerous states,

12) in the treatment of inflammatory complaints such as arthritis,

13) in the treatment of any general or skin complaint of viral origin,such as Kaposi's syndrome,

14) in the prevention or treatment of alopecia,

15) in the treatment of dermatological or general complaints having animmunological component,

16) in the treatment of complaints of the cardiovascular system such asarteriosclerosis, or hypertension, as well as insulin-independentdiabetes,

17) in the treatment of skin disorders due to exposure to UV radiation.

In the therapeutic fields mentioned above, the compounds according tothe invention may advantageously be employed in combination with othercompounds having retinoid-type activity, with D vitamins or derivativesthereof, with corticosteroids, with anti-free-radical agents, α-hydroxyor α-keto acids or derivatives thereof, or alternatively withion-channel blockers. The expression D vitamins or derivatives thereofis understood to refer, for example, to derivatives of vitamin D₂ or D₃and in particular 1,25-dihydroxyvitamin D₃. The expressionanti-free-radical agents is understood to refer, for example, toα-tocopherol, superoxide dismutase, ubiquinol or certain metal-chelatingagents. The expression α-hydroxy or α-keto acids or derivatives thereofis understood to refer, for example, to lactic acid, malic acid, citricacid, glycolic acid, mandelic acid, tartaric acid, glyceric acid orascorbic acid or salts, amides or esters thereof. Lastly, the expressionion-channel blockers is understood to refer, for example, to Minoxidil(2,4-diamino-6-piperidinopyrimidine 3-oxide) and derivatives thereof.

The subject of the present invention is also medicinal compositionscontaining at least one compound of formula (I) or (II) as definedabove, one of the optical or geometric isomers thereof or one of thesalts thereof.

The subject of the present invention is thus a novel medicinalcomposition intended in particular for treating the abovementionedcomplaints, and which is characterized in that it comprises, in apharmaceutically acceptable support which is compatible with the mode ofadministration selected for this composition, at least one compound offormula (I) or (II), one of the optical or geometric isomers thereof orone of the salts thereof.

The compounds according to the invention may be administered enterally,parenterally, topically or ocularly.

Via the enteral route, the medicinal products may be in the form oftablets, gelatin capsules, sugar-coated tablets, syrups, suspensions,solutions, powders, granules, emulsions, microspheres or nanospheres orpolymeric or lipid vesicles which allow controlled release. Via theparenteral route, the compositions may be in the form of solutions orsuspensions for infusion or for injection.

The compounds according to the invention are generally administered at adaily dose of about 0.01 mg/kg to 100 mg/kg of body weight, taken in 1to 3 doses.

Via the topical route, the pharmaceutical compositions based oncompounds according to the invention are more particularly intended fortreating the skin and mucous membranes and may, in this case, be in theform of ointments, creams, milks, salves, powders, impregnated pads,solutions, gels, sprays, lotions or suspensions. They may also be in theform of microspheres or nanospheres or polymeric or lipid vesicles orpolymeric patches and hydrogels which allow controlled release. Thesetopical-route compositions may moreover be either in anhydrous form orin an aqueous form, depending on the clinical indication.

Via the ocular route, they are mainly eyedrops.

These compositions for topical or ocular use contain at least onecompound of formula (I) or (II) as defined above, or one of the opticalor geometric isomers thereof, or alternatively one of the salts thereof,at a concentration preferably of between 0.001% and 5% by weightrelative to the total weight of the composition.

The compounds of formula (I) or (II) according to the invention alsofind an application in the cosmetic field, in particular in body andhair hygiene and especially for treating skin-types with a tendencytowards acne, for promoting the regrowth of the hair, for combating hairloss, for controlling the greasy appearance of the skin or the hair, inprotection against the harmful effects of sunlight or in the treatmentof physiologically dry skin-types, and for preventing and/or combatinglight-induced or chronological ageing.

In the cosmetic field, the compounds according to the invention may alsoadvantageously be employed in combination with other compounds havingretinoid-type activity, with D vitamins or derivatives thereof, withcorticosteroids, with anti-free-radical agents, α-hydroxy or α-ketoacids or derivatives thereof, or alternatively with ion-channelblockers, all of these different products being as defined above.

The present invention is thus also directed towards a cosmeticcomposition which is characterized in that it comprises, in acosmetically acceptable support which is suitable for topicalapplication, at least one compound of formula (I) or (II) as definedabove, or one of the optical or geometric isomers thereof or one of thesalts thereof, it being possible for this cosmetic composition to be inthe form of a cream, a milk, a lotion, a gel, microspheres ornanospheres or polymeric or lipid vesicles, a soap or a shampoo.

The concentration of compound of formula (I) or (II) in the cosmeticcompositions according to the invention is advantageously between 0.001%and 3% by weight relative to the composition as a whole.

The medicinal and cosmetic compositions according to the invention mayalso contain inert additives or even pharmacodynamically or cosmeticallyactive additives or combinations of these additives and, in particular,wetting agents; depigmenting agents such as hydroquinone, azelaic acid,caffeic acid or kojic acid; emollients; moisturizing agents such asglycerol, PEG 400, thiamorpholinone and derivatives thereof, oralternatively urea; anti-seborrhoea or anti-acne agents such asS-carboxymethylcysteine, S-benzylcysteamine, the salts and thederivatives thereof, or benzoyl peroxide; antibiotics such aserythromycin and esters thereof, neomycin, clindamycin and estersthereof, and tetracyclines; antifungal agents such as ketoconazole or4,5-polymethylene-3-isothiazolidones; agents for promoting the regrowthof the hair, such as minoxidil (2,4-diamino-6-piperidinopyrimidine3-oxide) and derivatives thereof, diazoxide(7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) and phenytoin(5,4-diphenylimidazolidine-2,4-dione); non-steroidal anti-inflammatoryagents; carotenoids and, in particular, β-carotene; anti-psoriaticagents such as anthraline and derivatives thereof and, lastly,eicosa-5,8,11,14-tetraynoic acid and eicosa-5,8,11-triynoic acid, theesters and the amides thereof.

The compositions according to the invention may also containflavour-enhancing agents, preserving agents such as para-hydroxybenzoicacid esters, stabilizing agents, moisture regulators, pH regulators,osmotic pressure modifiers, emulsifying agents, UV-A and UV-B screeningagents, and antioxidants such as α-tocopherol, butylhydroxyanisole orbutylhydroxytoluene.

Several examples of the production of active compounds of formula (I) or(II) according to the invention, as well as various solid formulationsbased on such compounds, will now be given by way of illustration andwith no limitation. Hereinabove and hereinbelow the percentages givenare by weight unless indicated otherwise.

EXAMPLE 14-[3-(3,5-Di-tert-butyl-4-oxo-2,5-cyclohexadien-1-ylidene)-1-propynyl]benzoicacid

(a) 3,5-Di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)benzaldehyde

12.3 g (52 mmol) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 100 mlof THF are introduced into a round-bottomed flask. 10 ml (58 mmol) ofdiisopropylethylamine and 10.3 ml (58 mmol) of2-trimethylsilylethoxymethane chloride are added successively and themixture is refluxed for three hours. The reaction medium is poured intowater and extracted with ethyl ether, and the organic phase is separatedout after settling has taken place, dried over magnesium sulphate andevaporated. The residue obtained is purified by chromatography on acolumn of silica eluted with a mixture of ethyl acetate and hexane(3/97% by volume). After evaporation of the solvents, 15.6 g (82%) ofthe expected product are collected in the form of a colourless oil.

(b)α-Trimethylsilylethynyl-3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)benzenemethanol

6.6 ml (46.5 mmol) of trimethylsilylacetylene and 50 ml of THF areintroduced into a three-necked flask. A solution of 18.6 ml (46.5 mmol)of n-butyllithium (2.5 M in hexane) is added dropwise at −78° C. andunder a stream of nitrogen, and the mixture is allowed to return to roomtemperature.

This solution is introduced dropwise into a solution of 15.4 g (42.3mmol) of 3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)benzaldehydein 50 ml of THF at −78° C. The reaction medium is allowed to return toroom temperature, poured into aqueous ammonium chloride solution andextracted with ethyl ether and the organic phase is separated out aftersettling has taken place, dried over magnesium sulphate and evaporated.18.5 g (95%) of the expected alcohol are obtained in the form of ayellow oil.

(c)α-Ethynyl-3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)benzenemethanol

18.5 g (40 mmol) ofα-trimethylsilylethynyl-3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)benzenemethanoland 50 ml of THF are introduced into a round-bottomed flask and 40 ml(44 mmol) of tetrabutylammonium fluoride solution (1.1 M in THF) areadded dropwise. The mixture is stirred at room temperature for one hour,the reaction medium is poured into water and extracted with ethyl etherand the organic phase is separated out after settling has taken place,dried over magnesium sulphate and evaporated. The residue obtained ispurified by chromatography on a column of silica eluted with a mixtureof ethyl acetate and hexane (5/95 by volume). After evaporation of thesolvents, 13.5 g (86%) ofα-ethynyl-3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)benzenemethanolare collected in the form of a colourless oil.

(d) Methyl4-{3-hydroxy-3-[3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)phenyl]-1-propynyl}benzoate

6 g (15.4 mmol) ofα-ethynyl-3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)benzenemethanol,4.1 g (15.4 mmol) of methyl 4-iodobenzoate and 50 ml of triethylamineare introduced into a three-necked flask. The reaction medium isdegassed with nitrogen for 30 minutes and 820 mg (1.2 mmol) ofbis(triphenylphosphine)palladium(II) chloride and 360 mg (1.9 mmol) ofcopper iodide are then added successively. The reaction medium isstirred at room temperature for four hours and evaporated to dryness,and the residue obtained is taken up in water and ethyl ether. Theorganic phase is separated out after settling has taken place, driedover magnesium sulphate and then evaporated. The residue obtained ispurified by chromatography on a column of silica eluted with a mixtureof dichloromethane and heptane (80/20% by volume); 6.7 g (84%) of methyl4-{3-hydroxy-3-[3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)phenyl]-1-propynyl}benzoateare collected, with a melting point of 91-2° C.

(e)4-{3-Hydroxy-3-[3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)phenyl]-1-propynyl}benzoicacid

2.4 g (4.6 mmol) of the above ester, 8.4.g (200 mmol) of lithiumhydroxide and 100 ml of THF are introduced into a round-bottomed flask.The reaction medium is refluxed for 18 hours and evaporated to dryness.The residue is taken up in water, acidified to pH 1 and extracted withethyl ether and the organic phase is separated out after settling hastaken place, dried over magnesium sulphate and evaporated. The residueis triturated from heptane and filtered and 2.2 g (94%) of the expectedacid are collected, with a melting point of 155-6° C.

(f)4-[3-(3,5-Di-tert-butyl-4-oxo-2,5-cyclohexadien-1-ylidene)-1-propynyl]benzoicacid

2.2 g (4.7 mmol) of4-{3-Hydroxy-3-[3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)phenyl]-1-propynyl}benzoicacid and 75 ml of dichloromethane are introduced into a three-neckedflask. 360 μl (4.7 mmol) of trifluoroacetic acid are added at −78° C.and the mixture is allowed to return to room temperature. The reactionmedium is poured into water and extracted with ethyl ether, and theorganic phase is separated out after settling has taken place, driedover magnesium sulphate and evaporated. The residue obtained istriturated from heptane, filtered and then dried. 1.6 g (90%) of4-[3-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-1-ylidene)-1-propynyl]benzoicacid are collected, with a melting point of 216-8° C.

EXAMPLE 2 4-[3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-1-propynyl]benzoicacid

756 mg (2 mmol) of4-[3-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-1-ylidene)-1-propynyl]benzoicacid and 50 ml of a mixture (50/50) of THF and methanol are introducedinto a three-necked flask. 152 mg (4 mmol) of sodium borohydride areadded at 0° C. and the mixture is allowed to return to room temperature.The reaction medium is poured into water and extracted with ethyl ether,and the organic phase is separated out after settling has taken place,dried over magnesium sulphate and evaporated. The residue obtained istriturated from refluxing heptane, filtered and dried. 510 mg (64%) of4-[3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-1-propynyl]benzoic acid arecollected, with a melting point of 198-9° C.

EXAMPLE 32-Hydroxy-4-[3-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-1-ylidene)-1-propynyl]benzoicacid

(a) Methyl2-hydroxy-4-{3-hydroxy-3-[3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)phenyl]-1-propynyl}benzoate

In a similar manner to Example 1(d), by reaction of 6.7 g (17.3 mmol) ofα-ethynyl-3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)benzenemethanolwith 4.8 g (17.3 mmol) of methyl 2-hydroxy-4-iodobenzoate, 8.5 g (91%)of the expected ester are obtained in the form of a yellow oil.

(b)2-Hydroxy-4-{3-hydroxy-3-[3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)phenyl]-1-propynyl}benzoicacid

In a similar manner to Example 1(e), starting with 8.4 g (15.5 mmol) ofmethyl2-hydroxy-4-{3-hydroxy-3-[3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)phenyl]-1-propynyl}benzoate,7.4 g (91%) of the expected acid are obtained, with a melting point of146-7° C.

(c)2-Hydroxy-4-[3-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-1-ylidene)-1-propynyl]benzoicacid

In a similar manner to Example 1(f), starting with 2.6 g (5 mmol) of2-hydroxy-4-{3-hydroxy-3-[3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)phenyl]-1-propynyl}benzoicacid, 1.7 g (89%) of2-hydroxy-4-[3-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-1-ylidene)-1-propynyl]benzoicacid are obtained, with a melting point of 203° C. with decomposition.

EXAMPLE 42-Hydroxy-4-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-propynyl]benzoicacid

In a similar manner to Example 2, starting with 1 g (2.6 mmol) of2-hydroxy-4-[3-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-1-ylidene)-1-propynyl]benzoicacid, 510 mg (51%) of2-hydroxy-4-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-propynyl]benzoicacid are obtained, with a melting point of 205-6° C.

EXAMPLE 54-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid

(a) Methyl 4-trimethylsilylethynylbenzoate

21.5 g (0.1 mol) of methyl 4-bromobenzoate, 300 ml of triethylamine anda mixture of 200 mg of palladium acetate and 400 mg oftriphenylphosphine are introduced into a three-necked flask under astream of nitrogen. 20 g (0.20 mol) of trimethylsilylacetylene are thenadded, the mixture is heated gradually to 90° C. over 1 hour and left atthis temperature for 5 hours. The reaction medium is cooled, the salt isfiltered off and the filtrate is evaporated. The residue is taken up in200 ml of hydrochloric acid (5%) and 400 ml of ethyl ether. The etherphase is separated out after settling has taken place, washed withwater, dried over magnesium sulphate and evaporated. The residueobtained is purified by chromatography on a column of silica eluted withdichloromethane. After evaporation of the solvents, 23 g (100%) of theexpected derivative are collected in the form of a colourless oil.

(b) Methyl4-[3-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate

8.4 g (36 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylchloride, 6.9 g (29.7 mmol) of methyl 4-trimethylsilylethynylbenzoateand 100 ml of dichloromethane are introduced into a round-bottomedflask. 16.8 g (125 mmol) of AlCl₃ are added portionwise at 0° C. and themixture is stirred at room temperature for 8 hours. The reaction mediumis poured into ice and extracted with dichloromethane, and the organicphase is separated out after settling has taken place, dried overmagnesium sulphate and evaporated. The residue obtained is purified bychromatography on a column of silica eluted with a mixture ofdichloromethane and hexane (50/50% by volume). 6.8 g (61%) of theexpected product are collected, with a melting point of 113-4° C.

(c) Methyl4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate

4.7 g (125 mmol) of the product obtained above and 100 ml of methanolare introduced into a round-bottomed flask. 5.7 g (150 mmol) ofCeCl₃.7H₂O and 530 mg (125 mmol) of sodium borohydride are successivelyadded, while cooling to 0° C., and the mixture is stirred at roomtemperature for 4 hours. The reaction medium is poured into awater/ethyl ether mixture and the organic phase is separated out aftersettling has taken place, washed with water, dried over magnesiumsulphate and evaporated. The residue obtained is triturated from 100 mlof hexane, filtered and dried. 4 g (85%) of the expected product arecollected, with a melting point of 142-3° C.

(d)4-[3-Hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid

In a similar manner to Example 1(e), starting with 1.7 g (4.5 mmol) ofthe above methyl ester, 1.3 g (79%) of4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid are obtained, with a melting point of 146-7° C.

(e)4-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid

2.1 ml (8.1 mmol) of BF₃.Et₂O (48%) and 50 ml of dichloromethane areintroduced into a three-necked flask under a stream of nitrogen. 2.6 ml(16.2 mmol) of triethylsilane are added at −20° C., followed by asolution of 1 g (2.7 mmol) of4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid in 30 ml of dichloromethane and the mixture is stirred at roomtemperature for 30 minutes. The reaction medium is poured into water andextracted with ethyl ether, and the organic phase is separated out aftersettling has taken place, dried over magnesium sulphate and evaporated.The residue obtained is purified on a column of silica eluted withdichloromethane. After evaporation of the solvents, 780 mg (82%) of4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid are collected, with a melting point of 167-8° C.

EXAMPLE 6 Methyl2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1propynyl]benzoate

(a)α-Trimethylsilylethynyl-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene)methanol

17.13 ml (0.121 mol) of trimethylsilylacetylene and 100 ml of THF areintroduced into a three-necked flask. A solution of 48.5 ml (0.121 mol)of n-butyllithium (2.5 M in hexane) is added dropwise at −78° C. under astream of nitrogen and the mixture is allowed to return to roomtemperature.

This solution is introduced dropwise into a solution of 23.8 g (0.11mol) of5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenecarboxaldehyde in100 ml of THF at −78° C. The reaction medium is allowed to return toroom temperature, poured into aqueous ammonium chloride solution andextracted with ethyl ether, and the organic phase is separated out aftersettling has taken place, dried over magnesium sulphate and evaporated.The residue obtained is purified by chromatography on a column of silicaeluted with a mixture of dichloromethane and hexane (50/50% by volume).After evaporation of the solvents, 29.9 g (86%) of the expected alcoholare collected in the form of a yellow oil.

(b)α-Ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene)methanol

29.9 g (95.2 mmol) ofα-trimethylsilylethynyl-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene)methanoland 100 ml of THF are introduced into a round-bottomed flask and 103.8ml (114.2 mmol) of tetrabutylammonium fluoride solution (1.1 M in THF)are added dropwise. The reaction medium is stirred at room temperaturefor one hour, poured into water and extracted with ethyl ether, and theorganic phase is separated out after settling has taken place, driedover magnesium sulphate and evaporated. The residue obtained is purifiedby chromatography on a column of silica eluted with a mixture of ethylacetate and hexane (1/4 by volume). After evaporation of the solvents,18.1 g (79%) ofα-ethynyl-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene)methanolare collected, with a melting point of 56-7° C.

(c) Methyl2-hydroxy-4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate

In a similar manner to Example 1(d), by reaction of 10.3 g (42.5 mmol)ofα-ethynyl-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene)methanolwith 11.8 g (42.5 mmol) of methyl 2-hydroxy-4-iodobenzoate, 13.6 g (82%)of the expected methyl ester are obtained, with a melting point of 92-3°C.

(d) Methyl2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate

In a similar manner to Example 5(e), starting with 1 g (2.6 mmol) of theabove methyl ester, 210 mg (22%) of methyl2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoateare obtained, with a melting point of 75-7° C.

EXAMPLE 72-Hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid

(a)2-Hydroxy-4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid

In a similar manner to Example 1(e), starting with 8.5 g (21.6 mmol) ofmethyl2-hydroxy-4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate,7.8 g (95%) of the expected acid are obtained, with a melting point of203° with decomposition.

(b)2-Hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid

In a similar manner to Example 5(e) starting with 1 g (2.6 mmol) of2-hydroxy-4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid, 820 mg (86%) of2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid are obtained, with a melting point of 178-80° C.

EXAMPLE 82-Hydroxy-4-[3-(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid

(a)3-Methoxyethoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-bromonaphthalene

720 mg (24 mmol) of sodium hydride (80% in oil) and 50 ml of DMF areintroduced into a three-necked flask under a stream of nitrogen. Asolution of 5.7 g (20 mmol) of3-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol dissolved in75 ml of DMF are added dropwise and the mixture is stirred until theevolution of gas has ceased. 6.8 ml (59.3 mmol) of methoxyethoxymethylchloride are then added at 0° C. and the mixture is stirred for fourhours. The reaction medium is poured into water and extracted with ethylether, and the organic phase is separated out after settling has takenplace, dried over magnesium sulphate and evaporated. 16.6 g (91%) of theexpected product are collected in the form of an oil.

(b)3-Methoxyethoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylcarboxaldehyde

16.3 g (44 mmol) of3-methoxyethoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-bromonaphthaleneand 50 ml of THF are introduced into a three-necked flask under a streamof nitrogen. 19.3 ml of n-butyllithium (2.5 M in hexane) are addeddropwise at −78° C. and the mixture is stirred for 30 minutes, followedby addition of 3.7 ml (48.4 mmol) of DMF, and the mixture is allowed toreturn to room temperature. The reaction medium is poured into aqueousammonium chloride solution and extracted with ethyl ether, and theorganic phase is separated out after settling has taken place, driedover magnesium sulphate and evaporated. 13.9 g (100%) of the expectedaldehyde are collected in the form of an oil.

c)α-Trimethylsilylethynyl-(3-methoxyethoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene)methanol

In a similar manner to Example 1(b), by reaction of 13.5 g (42.1 mmol)of3-methoxyethoxy-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylcarboxaldehydewith 7.1 ml (50.6 mmol) of trimethylsilylacetylene, 17.5 g (100%) of theexpected alcohol are obtained in the form of a yellow oil.

d)α-Ethynyl-(3-methoxyethoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene)methanol

In a similar manner to Example 1(c), starting with 17 g (40.6 mmol) ofα-trimethylsilylethynyl-(3-methoxyethoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene)methanol,12.4 g (88%) ofα-ethynyl-(3-methoxyethoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene)methanolare obtained in the form of an oil.

(e) Methyl2-hydroxy-4-[3-hydroxy-3-(3-methoxyethoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate

In a similar manner to Example 1(d), by reaction of 7.1 g (20.5 mmol) ofα-ethynyl-(3-methoxyethoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene)methanolwith 5.7 g (20.5 mmol) of methyl 2-hydroxy-4-iodobenzoate, 9.6 g (94%)of the methyl ester are obtained in the form of an oil.

(f)2-Hydroxy-4-[3-hydroxy-3-(3-methoxyethoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid

In a similar manner to Example 1(e), starting with 9 g (21.6 mmol) ofthe above methyl ester, 7.8 g (89%) of the expected acid are obtained,with a melting point of 106-8° C.

(g)2-Hydroxy-4-[3-(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid

In a similar manner to Example 5(e), starting with 1.7 g (3.5 mmol) of2-hydroxy-4-[3-hydroxy-3-(3-methoxyethoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid, 670 mg (50%) of the expected acid are obtained, with a meltingpoint of 216-7° C.

EXAMPLE 92-Hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzenemethanol

760 mg (2.2 mmol) of methyl2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoateand 20 ml of toluene are introduced into a three-necked flask under astream of nitrogen. 4.4 ml of diisobutylaluminium hydride (1 M intoluene) are added at −78° C. and the mixture is allowed to return toroom temperature. 9 ml of methanol and then 9 ml of hydrochloric acid (1N) are successively introduced. The reaction medium is poured into anethyl acetate/water mixture and the organic phase is separated out aftersettling has taken place, dried over magnesium sulphate and thenevaporated. The residue is purified by chromatography on a column ofsilica eluted with a mixture of ethyl acetate and heptane (50/50% byvolume). After evaporation of the solvents, 200 mg (30%) of the expectedalcohol are collected, with a melting point of 94-5° C.

EXAMPLE 10 Diethanolamine2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate

100 mg (2.76 mmol) of2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid and 5 ml of methanol are introduced into a round-bottomed flask and29 mg (2.76 mmol) of diethanolamine are added. The reaction medium isstirred for one hour and evaporated to dryness, and the residue obtainedis triturated from a mixture of heptane and ethyl ether (50/50). Thesolid is filtered off and dried. 100 mg (78%) of diethanolamine salt arecollected, with a melting point of 100-5° C.

EXAMPLE 11 Lithium2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate

In a similar manner to Example 10, by reaction of 200 mg (5.5 mmol) of2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid with 23 mg (5.5 mmol) of lithium hydroxide hydrate, 150 mg (74%) ofthe expected lithium salt are obtained, with a melting point of 225-9°C.

EXAMPLE 124-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-propynyl]benzoicacid

In a similar manner to Example 5(e), starting with 1.66 g (4.6 mmol) of4-[1-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-propynyl]benzoicacid (prepared in Example 10(b) of patent EP 0,661,258), 310 mg (19.5%)of4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-propynyl]benzoicacid are obtained, with a melting point of 159-60° C.

EXAMPLE 132-Hydroxy-4-[3-(4,4-dimethylthiochroman-6-yl)-1-propynyl]benzoic acid

In a similar manner to Example 5(e), starting with 750 mg (2 mmol) of2-hydroxy-4-[3-hydroxy-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl]benzoicacid (prepared in Example 19 of patent EP 0,661,258), and afterchromatography on a column of silica eluted with a mixture ofdichloromethane and methanol (80/20), 340 mg (28%) of2-hydroxy-4-[3-(4,4-dimethylthiochroman-6-yl)-1-propynyl]benzoic acidare obtained, with a melting point of 195-6° C.

EXAMPLE 142-Hydroxy-4-[3-(8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthytl)-1-propynyl]benzoicacid

(a) Methyl2-hydroxy-4-[3-oxo-3-(8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoate

12 g (54 mmol) of 8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthoyl chloride,14.7 g (59 mmol) of methyl 2-hydroxy-4-trimethylsilylethynylbenzoate(prepared in Example 5(a) of patent EP 0,661,258) and 200 ml ofdichloromethane are introduced into a round-bottomed flask. 21.6 g (162mmol) of AlCl₃ are added portionwise at 0° C. and the mixture is stirredat room temperature for 8 hours. The reaction medium is poured into iceand extracted with dichloromethane, and the organic phase is separatedout after settling has taken place, dried over magnesium sulphate andevaporated. The residue obtained is purified by chromatography on acolumn of silica eluted with a mixture of dichloromethane and hexane(50/50). 12.5 g (64%) of the expected product are collected, with amelting point of 114-6° C.

(b) Methyl2-hydroxy-4-[3-hydroxy-3-(8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoate

7.95 g (22 mol) of methyl2-hydroxy-4-[3-oxo-3-(8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoate,150 ml of THF and 20 ml of methanol are introduced into a round-bottomedflask. 660 mg (17.4 mmol) of sodium borohydride are added portionwiseand the mixture is stirred at room temperature for two hours. Thereaction medium is poured into ice-water, neutralized with hydrochloricacid and extracted with ethyl acetate, and the organic phase isseparated out after settling has taken place, washed with water, driedover magnesium sulphate and evaporated. The residue obtained is purifiedby chromatography on a column of silica eluted with a mixture of heptaneand ethyl acetate (80/20). After evaporation of the solvents, 3.8 g(47.5%) of the expected product are collected in the form of an oil.

(c) Methyl2-hydroxy-4-[3-(8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoate

In a similar manner to Example 5(e), starting with 4 g (11 m mol) of theabove methyl ester, 1.13 g (29.5%) of methyl2-hydroxy-4-[3-(8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoateare obtained in the form of an orange-coloured oil.

(d)2-Hydroxy-4-[3-(8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoicacid

In a similar manner to Example 1(e), starting with 1 g (2.9 mmol) of theabove methyl ester, 370 mg (39%) of2-hydroxy-4-[3-(8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoicacid are obtained, with a melting point of 185-7° C.

EXAMPLE 152-Hydroxy-4-[3-(5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoicacid

(a) Methyl2-hydroxy-4-[3-oxo-3-(5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoate

In a similar manner to Example 14(a), by reaction of 4.7 g (21 mmol) of5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthoyl chloride with 5.7 g (22.8mmol) of methyl 2-hydroxy-4-trimethylsilylethynylbenzoate (prepared inExample 5(a) of patent EP 0,661,258), 5.14 g (68.5%) of the expectedmethyl ester are obtained, with a melting point of 89-90° C.

(b) Methyl2-hydroxy-4-[3-hydroxy-3-(5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoate

In a similar manner to Example 14(b), starting with 2.4 g (6.6 mmol) ofmethyl2-hydroxy-4-[3-oxo-3-(5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoate,1.6 g (67%) of methyl2-hydroxy-4-[3-hydroxy-3-(5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoateare obtained in the form of an orange-coloured oil.

(c)2-Hydroxy-4-[3-hydroxy-3-(5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoicacid

In a similar manner to Example 1(e), starting with 1.61 g (4.4 mmol) ofthe above methyl ester, 1.2 g (77.4%) of the expected acid are obtained,with a melting point of 141-2° C.

(d)2-Hydroxy-4-[3-(5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoicacid

In a similar manner to Example 5(e), starting with 580 mg (1.65 mmol) of2-hydroxy-4-[3-hydroxy-3-(5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoicacid, 470 mg (85%) of2-hydroxy-4-[3-(5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoicacid are obtained, with a melting point of 152-3° C.

EXAMPLE 16 Ethyl4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate

(a) Methoxyallene

210 ml (2.5 mol) of propargyl methyl ether and 12 g (0.11 mol) ofpotassium tert-butoxide are introduced into a three-necked flask underargon. The reaction medium is refluxed for three hours and distilled atatmospheric pressure, and the fraction passing at 51° C. is collected.153.5 g (88%) of the expected product are obtained in the form of acolourless oil.

(b) 3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propyne

20 g (0.82 mol) of magnesium activated with 0.1 ml of dibromoethane areintroduced into a four litre reactor under a stream of nitrogen. Asolution of 200 g (0.75 mol) of2-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene is addeddropwise so as to maintain the reflux of the THF and the mixture isstirred at 50° C. for two hours. The reaction medium is then cooled to−5° C. and 1.2 g (8.2 mmol) of CuBr are added and a solution of 58 g(0.82 mol) of methoxyallene in 100 ml of THF is introduced dropwise. Themixture is stirred for one hour at −5° C. and is then allowed to returnto room temperature and is stirred for two hours. The reaction medium ispoured into saturated ammonium chloride solution and extracted withethyl acetate, and the organic phase is separated out after settling hastaken place, dried over magnesium sulphate and evaporated. The oilobtained is distilled at 0.02 mm Hg and the fraction passing at 95-100°C. is collected. 79 g (47%) of the expected product are obtained in theform of a colourless oil.

(c) Ethyl4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate

7.4 g (32.7 mmol) of3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propyne, 8.2 g(29.7 mmol) of ethyl 4-iodobenzoate and 50 ml of triethylamine areintroduced into a three-necked flask under a stream of nitrogen. Thereaction medium is degassed by bubbling nitrogen through, 360 mg (0.5mmol) of bis(triphenylphosphine)palladium(II) chloride and 130 mg ofcopper iodide are introduced and the mixture is stirred at roomtemperature for eight hours. The reaction medium is evaporated todryness, the residue is taken up in ethyl acetate and hydrochloric acid(1 N) and the organic phase is separated out after settling has takenplace, dried over magnesium sulphate and evaporated. The residue ispurified by chromatography on a column of silica eluted with a mixtureof heptane and ethyl acetate (70/30). After evaporation of the solvents,a solid is collected which is triturated from heptane, filtered anddried. 9.3 g (84%) of the expected ethyl ester are collected, with amelting point of 59-60° C.

EXAMPLE 174-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamide

(a)4-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid

In a similar manner to Example 16(c), by reaction of 8 g (35.3 mmol) of3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propyne with 8 g(32.1 mmol) of 4-iodobenzoic acid, 10.4 g (94%) of the expected acid areobtained, with a melting point of 167-8° C.

(b)4-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoylchloride

2.9 g (8.3 mmol) of4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid and 100 ml of dichloromethane are introduced into a round-bottomedflask under a stream of nitrogen and 2.4 ml (12.1 mmol) ofdicyclohexylamine are added dropwise. The mixture is stirred at roomtemperature for one hour, 1.2 ml (11.7 mmol) of thionyl chloride areadded dropwise and the mixture is stirred for one hour. The reactionmedium is evaporated to dryness, the residue is taken up in ethyl ether,the dicyclohexylamine salt is filtered off and the filtrate isevaporated. 3 g (100%) of the crude acid chloride are collected, whichproduct will be used in its current state for the rest of the synthesis.

(c)4-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamide

3 g (8.3 mmol) of the above acid chloride dissolved in 100 ml of THF areintroduced into a round-bottomed flask, 1 ml (9.1 mmol) of aqueousammonia (32%) is added and the mixture is stirred at room temperaturefor one hour. The reaction medium is poured into water and extractedwith dichloromethane, and the organic phase is separated out aftersettling has taken place, washed with water, dried over magnesiumsulphate and evaporated. The solid obtained is triturated from heptane,filtered and dried. 2.5 g (87%) of4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamideare collected, with a melting point of 207-8° C.

EXAMPLE 18N-Ethyl-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamide

In a similar manner to Example 17(b), by reaction of 3 g (8.3 mmol) of4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoylchloride with 650 μl (10 mmol) of ethylamine (70%), 1.84 g (59.4%) ofthe expected ethyl amide are obtained, with a melting point of 128-9° C.

EXAMPLE 194-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid morpholide

In a similar manner to Example 17(b), by reaction of 1.25 g (3.4 mmol)of4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoylchloride with 320 μl (3.8 mmol) of morpholine, 430 mg (31%) of4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid morpholide are obtained, with a melting point of 98-9° C.

EXAMPLE 20N-(4-Hydroxyphenyl)-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamide

In a similar manner to Example 17(b), by reaction of 3 g (8.3 mmol) of4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoylchloride with 1 g (9.2 mmol) of 4-aminophenol, 1.94 g (54%) ofN-(4-hydroxyphenyl)-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamideare obtained, with a melting point of 159-60° C.

EXAMPLE 214-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzenemethanol

In a similar manner to Example 16(c), by reaction of 3.67 g (16.2 mmol)of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propyne with3.45 g (14.8 mmol) of 4-iodobenzenemethanol, 4.9 g (100%) of4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzenemethanolare obtained in the form of a viscous orange oil.

¹H NMR (CDCl³, 250 MHz) 1.27 (6H, s), 1.29 (6H, s), 1.68 (4H, s), 3.77(2H, s), 4.67 (2H, d), 7.17 (1H Ar, dd), 7.27 (2H Ar, d), 7.30 (2H Ar,d), 7.42 (2H Ar, c).

EXAMPLE 224-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzaldehyde

1.3 g (4 mmol) of4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzenemethanoland 20 ml of dichloromethane are introduced into a round-bottomed flaskand 3.4 g (39.2 mmol) of manganese oxide are added. The mixture isstirred at room temperature for eight hours. Magnesium sulphate is addedto the reaction medium, the mixture is filtered and the filtrate isevaporated. The residue obtained is purified by chromatography on acolumn of silica eluted with a mixture of ethyl acetate and heptane(10/90). After evaporation of the solvents, 930 mg (29.5%) of4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzaldehydeare collected in the form of a yellow oil.

¹H NMR (CDCl₃, 250 MHz) 1.28 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 3.81(2H, s), 7.20 (1H Ar, dd), 7.31 (2H Ar, c), 7.59 (2H Ar, d), 7.80 (2HAr, d), 9.99 (1H, s).

EXAMPLE 234-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]phenol

In a similar manner to Example 16(c), by reaction of 1.13 g (5 mmol) of3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propyne with 1 g(4.5 mmol) of 4-iodophenol, 1.28 g (88%) of4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]phenolare obtained in the form of a viscous orange-red oil.

¹H NMR (CDCl₃, 250 MHz) 1.27 (6H, s), 1.29 (6H, s), 1.68 (4H, s), 3.75(2H, s), 5.05 (1H, s), 6.76 (2H, d), 7.20 (1H Ar, dd), 7.25 (1H, d),7.31 (3H Ar, c).

EXAMPLE 244-[3-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]toluene

In a similar manner to Example 16(c), by reaction of 1.62 g (7.15 mmol)of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propyne with1.42 g (6.5 mmol) of 4-iodotoluene, 1.29 g (63%) of4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]tolueneare obtained in the form of a yellowish oil.

¹H NMR (CDCl₃, 250 MHz) 1.27 (6H, s), 1.29 (6H, s), 1.69 (4H, s), 2.33(3H, s), 3.81 (2H, s), 7.20 (1H Ar, dd), 7.31 (2H Ar, c), 7.59 (2H Ar,d), 7.80 (2H Ar, d).

EXAMPLE 25 Hexyl4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate

2 g (5.8 mmol) of4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid, 30 ml of DMF, 2 drops of 15-crown-5 and 2 g (23.8 mmol) of sodiumbicarbonate are introduced into a round-bottomed flask. 3.1 ml (20.8mmol) of 1-iodohexane are added and the mixture is stirred at roomtemperature for 24 hours. The reaction medium is poured into water andextracted with ethyl acetate and the organic phase is separated outafter settling has taken place, washed with water, dried over magnesiumsulphate and evaporated. 2 g (80%) of the expected hexyl ester arecollected in the form of a pale red oil.

¹H NMR (CDCl₃, 250 MHz) 0.9 (3H, t), 1.27 (6H, s), 1.29 (6H, s), 1.34(6H, c), 1.66 (4H, s), 1.72 (2H, m), 3.81 (2H, s), 4.30 (2H, t), 7.20(1H Ar, dd), 7.31 (2H Ar, c), 7.50 (2H Ar, d), 7.95 (2H Ar, d).

EXAMPLE 26N-Hydroxy-2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamide

(a) N-Hydroxy-2-hydroxy-4-iodobenzamide

23.3 g (84 mmol) of methyl 2-hydroxy-4-iodobenzoate and 360 ml of sodiumhydroxide solution (1 N) are introduced into a three-necked flask undera stream of nitrogen. 8 g (113 mmol) of hydroxylamine hydrochloride areadded and the mixture is stirred at room temperature for two hours. Thereaction medium is adjusted to pH 7-8 with concentrated hydrochloricacid and the solid is filtered off. The solid is dissolved in ethylacetate and washed with water, and the organic phase is separated outafter settling has taken place, dried over magnesium sulphate andevaporated. The residue is triturated from heptane, filtered and dried.17.6 g (71.5%) of the expected product are collected, with a meltingpoint of 195-6° C.

(b)N-Hydroxy-2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamide

In a similar manner to Example 16(c), by reaction of 4 g (17.7 mmol) of3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propyne with 4.1g (14.7 mmol) of N-hydroxy-2-hydroxy-4-iodobenzamide, 550 mg (10%) ofN-hydroxy-2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamideare obtained, with a melting point of 119-20° C.

EXAMPLE 272-Methyl-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid

In a similar manner to Example 16(c), by reaction of 10 g (44.2 mmol) of3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propyne with 6.5g (29.5 mmol) of 4-bromo-2-methylbenzoic acid, 1.18 g (11%) of2-methyl-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid are obtained, with a melting point of 149-50° C.

EXAMPLE 283-Methyl-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid

In a similar manner to Example 16(c), by reaction of 10 g (44.2 mmol) of3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propyne with 6.5g (29.5 mmol) of 4-bromo-3-methylbenzoic acid, 1.1 g (11%) of3-methyl-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid are obtained, with a melting point of 196-7° C.

EXAMPLE 296-[3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)propa-1,2-dienyl]nicotinicacid

(a) Methyl6-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)propa-1,2-dienyl]nicotinate

In a similar manner to Example 16(c), by reaction of 920 mg (4.1 mmol)of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propyne with1.1 g (4.2 mmol) of methyl 4-iodonicotinate, 260 mg (18%) of methyl6-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)propa-1,2-dienyl]nicotinateare obtained in the form of an orange-coloured oil.

¹H NMR (CDCl₃, 250 MHz) 1.34 (12H, s), 1.75 (4H, s), 3.87 (3H, s), 6.56(1H, d), 6.92 (1H, d), 7.19 (1H, d), 7.29 (1H, dd), 7.42 (2H, t), 7.50(1H, d), 9.10 (1H, s).

(b)6-[3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)propa-1,2-dienyl]-3-nicotinicacid

370 mg (1 mmol) of the above methyl ester, 10 ml of THF and 5 ml ofmethanolic sodium hydroxide solution (2 N) are introduced into around-bottomed flask. The mixture is heated at 40° C. for one hour andevaporated to dryness, the residue is taken up in water, the pH isadjusted to 5 with hydrochloric acid, the mixture is extracted withethyl acetate and the organic phase is separated out after settling hastaken place, dried over magnesium sulphate and evaporated. The residueis triturated from heptane, filtered and dried. 240 mg (66%) of theexpected acid are collected, with a melting point of 224-5° C.

EXAMPLE 304-[3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-nahthyl)propa-1,2-dienyl]benzoicacid

6.02 g (16 mmol) of ethyl4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate,5 ml of methanol, 5 ml of THF and 50 ml of heptane are introduced into around-bottomed flask. 850 mg of sodium hydroxide are added and themixture is refluxed for one hour. The reaction medium is poured intowater, adjusted to pH 1 with hydrochloric acid and extracted with ethylacetate, and the organic phase is separated out after settling has takenplace, dried over magnesium sulphate and evaporated. The residueobtained is triturated from ethyl alcohol, filtered and dried. 1.37 g(24.5%) of4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)propa-1,2-dienyl]benzoicacid are collected, with a melting point of 227-8° C.

EXAMPLE 312-Hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-butynyl]benzoicacid

In a similar manner to Example 5(e), starting with 1 g (2.55 mmol) of2-hydroxy-4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-butynyl]benzoicacid (prepared in Example 30 of patent EP 0,661,258), 450 mg (47%) of2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-butynyl]benzoicacid are obtained, with a melting point of 191-2° C.

EXAMPLE 32

Various specific formulations based on compounds according to theinvention are illustrated in this example.

A - ORAL ROUTE (a) 0.2 g tablet Compound of Example 2 0.001 g Starch0.114 g Dicalcium phosphate 0.020 g Silica 0.020 g Lactose 0.030 g Talc0.010 g Magnesium stearate 0.005 g (b) Drinkable suspension in 5 mlampules Compound of Example 6 0.001 g Glycerol 0.500 g 70% Sorbitol0.500 g Sodium saccharinate 0.010 g Methyl para-hydroxybenzoate 0.040 gFlavouring qs Purified water qs 5 ml (c) 0.8 g tablet Compound ofExample 5 0.500 g Pregelatinized starch 0.100 g Microcrystallinecellulose 0.115 g Lactose 0.075 g Magnesium stearate 0.010 g (d)Drinkable suspension in 10 ml ampules Compound of Example 2 0.05 gGlycerol 1.000 g 79% Sorbitol 1.000 g Sodium saccharinate 0.010 g Methylpara-hydroxybenzoate 0.080 g Flavouring qs Purified water qs 10 ml B -TOPICAL ROUTE (a) Ointment Compound of Example 9 0.020 g Isopropylmyristate 81.700 g Liquid petroleum jelly 9.100 g Silica (“Aerosil 200”sold by Degussa) 9.180 g (b) Ointment Compound of Example 7 0.300 gWhite petroleum jelly codex 100 g (c) Nonionic water-in-oil creamCompound of Example 25 0.100 g Mixture of emulsifying lanolin alcohols,39.900 g waxes and oils (“anhydrous eucerin” sold by BDF) Methylpara-hydroxybenzoate 0.075 g Propyl para-hydroxybenzoate 0.075 g Steriledemineralized water qs 100 g (d) Lotion Compound of Example 8 0.100 gPolyethylene glycol (PEG 400) 69.900 g 95% Ethanol 30.000 g (e)Hydrophobic ointment Coumpound of Example 20 0.300 g Isopropyl myristate36.400 g Silicone oil (“Rhodorsil 47 V 300” 36.400 g sold byRhône-Poulenc) Beeswax 13.600 g Silicone oil (“Abil 300,000 cst” 100 gsold by Goldschmidt) (f) Nonionic oil-in-water cream Compound of Example30 0.500 g Cetyl alcohol 4.000 g Glyceryl monostearate 2.500 g PEG-50stearate 2.500 g Karite butter 9.200 g Propylene glycol 2.000 g Methylpara-hydroxybenzoate 0.075 g Propyl para-hydroxybenzoate 0.075 g Steriledemineralized water 100 g

What is claimed is:
 1. A propynyl biaromatic compound, having thegeneral formula (I) below:

in which: R₁ is (i) the —CH₃ radical (ii) the radical —CH₂—O—R₆ (iii)the radical —O—R₆, or (iv) the radical —CO—R₇ R₆ and R₇ having themeanings given below, Ar is a radical selected from the group consistingof (a)-(e) below:

 R₅ and R₆ have the meanings given below, X is a radical of formula:

 R₈ and R₉ have the meanings given below, R₂ and R₃, which may beidentical or different, are selected from the following: (i) a hydrogenatom, (ii) a linear or branched alkyl radical having from 1 to 20 carbonatoms, (iii) a radical —OR₆, (iv) a radical —SR₆, R₆ is defined below,wherein R₂ and R₃, taken together, may form, with the adjacent aromaticring, a 5- or 6-membered ring optionally substituted with methyl groupsand/or optionally interrupted by an oxygen or sulfur atom, wherein R₂and R₃ cannot simultaneously have the meanings (i), (iii) and (iv)mentioned above, R₄ and R₅, which may be identical or different, arehydrogen atom, a halogen atom, a linear or a branched alkyl radicalhaving from 1 to 20 carbon atoms or a radical —OR₆, wherein if R₄ is ahydroxyl radical, then R₂ and R₃ form, with the adjacent aromatic ring,a 5- or 6-membered ring which optionally is substituted with methylgroups and/or optionally interrupted by an oxygen or a sulfur atom, R₆is a hydrogen atom, a lower alkyl radical or a radical —COR₁₀ R₁₀ isdefined below, R₇ is selected from the following: (a) a hydrogen atom(b) a lower alkyl radical (c) a radical of formula:

 wherein R′ and R″ are defined below, (d) a radical —OR₁₁, (e) a radical—NHOR₆, R₁₁ is defined below, R₈ and R₉, if considered separately, arethe same and are either a hydrogen atom or a radical —OR₁₀, or R₈ and R₉are different, and one of them is a hydrogen atom and the other is alower alkyl radical, or, R₈ and R₉ together form a ring —Y—(CH₂)_(n)—Y—,with Y representing an oxygen or a sulfur atom and with n equal to 2 or3, R₁₀ is a lower alkyl radical, R₁₁ is a hydrogen atom, a linear orbranched alkyl radical having from 1 to 20 carbon atoms, an alkenylradical, a mono- or polyhydroxyalkyl radical, an optionally substitutedaryl or aralkyl radical, a sugar residue or an amino acid or peptideresidue, R′ and R″, which may be identical or different, are selectedfrom a hydrogen atom, a lower alkyl radical, a mono- or polyhydroxyalkylradical, an optionally substituted aryl radical or an amino acid orsugar residue, or alternatively, taken together, form a heterocycle, ora salt or optical or geometric isomer of said compound.
 2. A compoundhaving the general formula (II) below:

in which R₁ and Ar are defined according to claim 1 and wherein R′₂ andR′₄, which may be identical or different, are each a linear or branchedalkyl radical having from 1 to 20 carbon atoms.
 3. A compound accordingto claim 1, wherein said compound is selected from the group consistingof alkali metal, alkaline earth metal, zinc, and organic amine salts. 4.A compound according to claim 1, which is selected from the groupconsisting of:4-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-propynyl]benzoic acid,2-hydroxy-4-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-propynyl]benzoicacid,4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid, methyl2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate,2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid,2-hydroxy-4-[3-(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid,2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzenemethanol,diethanolamine2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate,lithium2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate,4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-propynyl]benzoicacid, 2-hydroxy-4-[3-(4,4-dimethylthiochroman-6-yl)-1-propynyl]benzoicacid,2-hydroxy-4-[3-(8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoicacid,2-hydroxy-4-[3-(5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoicacid, ethyl4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate,4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamide,N-ethyl-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamide,4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid morpholide,N-(4-hydroxyphenyl)-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamide,4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzaldehyde,4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]phenol,[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzenemethanol,4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]toluene,hexyl4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate,N-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamide,N-hydroxy-2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamide,2-methyl-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid,3-methyl-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoicacid,6-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)propa-1,2-dienyl]nicotinicacid,4-[3-(5,5,8,8-tetra-methyl-5,6,7,8-tetrahydro-2-naphthyl)propa-1,2-dienyl]benzoicacid,2-hydroxy-4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)propa-1,2-dienyl]benzoicacid,2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-butynyl]benzoicacid,5-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]-2-pyridinecarboxylicacid,4-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoicacid,2-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]-4-thiophenecarboxylicacid,2-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]-4-thiophenecarboxylicacid, 2-hydroxy-4-[3-(3-tert-butyl-4-methoxyphenyl)-1-propynyl]benzoicacid, 2-hydroxy-4-[3-(3-tert-butyl-4-hydroxyphenyl)-1-propynyl]benzoicacid.
 5. A compound according to claim 3, selected from the groupconsisting of:4-[3-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-1-ylidene)-1-propynyl]benzoicacid, and2-hydroxy-4-[3-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-1-ylidene)-1-propynyl]benzoicacid.
 6. A compound according to claim 1, which has at least one of thefollowing characteristics: R₁ represents the radical —CO—R₇, Arrepresents the radicals of formula (a) or (e).
 7. A compound accordingto one of claim 1, in which R₈ and R₉ are both hydrogen atoms or one ofthem represents a hydrogen atom and the other represents a lower alkylradical.
 8. A method of therapy comprising administration of atherapeutically effective amount of at least one compound of formula (I)or (II) according to claim
 1. 9. A method for therapy which involves theadministration of a therapeutically effective amount of a compoundaccording to claim 1, wherein the condition treated is selected from thegroup consisting of dermatological conditions, inflammatory conditions,opthamological disorders, cancerous or precancerous conditions,alopecia, cardiovascular conditions, and insulin-dependent diabetes. 10.The method of claim 9, wherein said dermatological condition is selectedfrom the group consisting of: (i) conditions associated withkeratinization, which optionally are associated with differentiationand/or proliferation; (ii) keratinization disorders having animmunological and/or immunoallergic component; (iii) dermal andepidermal proliferations, benign or malignant, which are of viral ornon-viral origin; (iv) bullosis or collagen disorders; (v) chronologicalor UV-induced aging of the skin; (vi) actinic keratoses andpigmentation; (vii) stigmata of epidermal and/or dermal atrophy inducedby local or systemic corticosteroids; (viii) cutaneous atrophy; (ix)cicatrization disorders; (x) vibices; (xi) promotion of cicatrization;(xii) disorders of sebaceous function; (xiii) general skin complaints oforal origin; (xiv) immunological dermatological conditions; and (xv)skin disorders associated with UV radiation exposure.
 11. The method ofclaim 9, wherein said disorder is selected from the group consisting ofcommon acne, comedones, polymorphonuclear leukocytes, acne rosacea,nodulocystic acne, acne conglobata, senile acne, solar,medication-related acne, occupational acne, ichthyosis, ichthyosiformstates, Darier's disease, palmoplantar keratoderma, leucoplasias andleucoplasiform states, cutaneous or mucous (buccal) lichen; psoriasis,cutaneous, mucous or ungual psoriasis, psoriatic rheumatism, eczema,respiratory atopy, gingival hypertrophy, common warts, flat warts,verruciform epidermodysplasia, oral or florid papillomatoses,proliferations induced by ultraviolet radiation, basocellular orspinocellular epithelioma; corneopathies, promyelocytic leukemia,arthritis, arteriosclerosis, and hypertension.
 12. A pharmaceuticalcomposition containing a therapeutically effective amount of a compoundaccording to claim
 1. 13. A composition according to claim 12, whereinthe concentration of said compound is between 0.001% and 5% by weightrelative to the composition as a whole.
 14. A cosmetic composition whichcomprises, in a cosmetically acceptable carrier or excipient, acosmetically effective amount of at least one of the compounds asdefined in claim
 1. 15. A cosmetic composition according to claim 14,wherein the concentration of said compound is between 0.001% and 3% byweight relative to the composition as a whole.
 16. A method of hygienecomprising administering an effective amount of a cosmetic compositionas defined in claim 14, for body or hair hygiene.
 17. A compoundaccording to claim 2, which is an alkali metal, alkaline earth metal,zinc, or organic amine salt.
 18. A compound according to claim 2,wherein at least one of the following is satisfied: R₁ is —CO—R₇, and Aris a radical of formula (a) or (e).
 19. A medicinal compositioncontaining a medicinally effective amount of at least one compoundhaving formula (II) according to claim
 2. 20. A method of therapy whichinvolves the administration of a therapeutically effective amount of acompound according to claim 2, wherein the condition treated is selectedfrom the group consisting of dermatological conditions, inflammatoryconditions, opthamological disorders, cancerous or precancerousconditions, alopecia, cardiovascular conditions, and insulin-dependentdiabetes.
 21. The method of claim 20, wherein said dermatologicalcondition is selected from the group consisting of: (i) conditionsassociated with keratinization, which optionally are associated withdifferentiation and/or proliferation; (ii) keratinization disordershaving an immunological and/or immunoallergic component; (iii) dermaland epidermal proliferations, benign or malignant, which are of viral ornon-viral origin; (iv) bullosis or collagen disorders; (v) chronologicalor UV-induced aging of the skin; (vi) actinic keratoses andpigmentation; (vii) stigmata of epidermal and/or dermal atrophy inducedby local or systemic corticosteroids; (viii) cutaneous atrophy; (ix)cicatrization disorders; (x) vibices; (xi) promotion of cicatrization;(xii) disorders of sebaceous function; (xiii) general skin complaints oforal origin; (xiv) immunological dermatological conditions; and (xv)skin disorders associated with UV radiation exposure.
 22. The method ofclaim 20, wherein said disorder is selected from the group consisting ofcommon acne, comedones, polymorphonuclear leukocytes, acne rosacea,nodulocystic acne, acne conglobata, senile acne, solar,medication-related acne, occupational acne, ichthyosis, ichthyosiformstates, Darier's disease, palmoplantar keratoderma, leucoplasias andleucoplasiform states, cutaneous or mucous (buccal) lichen; psoriasis,cutaneous, mucous or ungual psoriasis, psoriatic rheumatism, eczema,respiratory atopy, gingival hypertrophy, common warts, flat warts,verruciform epidermodysplasia, oral or florid papillomatoses,proliferations induced by ultraviolet radiation, basocellular orspinocellular epithelioma; corneopathies, promyelocytic leukemia,arthritis, arteriosclerosis, and hypertension.
 23. A pharmaceuticalcomposition which comprises, in a pharmaceutically acceptable carrier, apharmaceutically effective amount of carrier at least one compoundaccording to claim
 2. 24. A composition according to claim 23, whereinthe concentration of said compound ranges from 0.001% and 5% by weightrelative to the composition as a whole.
 25. A cosmetic composition,which comprises, in a cosmetically acceptable carrier, at least onecompounds according to claim
 2. 26. A composition according to claim 25,wherein the concentration of said compound ranges from 0.001% and 3% byweight relative to the composition as a whole.
 27. A method of hygienecomprising administering an effective amount of a cosmetic compositionas defined in claim 25, for body or hair hygiene.
 28. The propynylbioaromatic compound of formula I, in claim 1 wherein R₂ and R₃ aretaken individually and are not both alkyl radicals.
 29. The propynylbioarmoatic compound of formual I, in claim 1, wherein R₂ and R₃together form with the adjacent aromatic ring a 5 or 6 membered ringoptionally substituted with methyl groups and interrupted by a sulfuratom.
 30. The propynyl bioaromatic compound of formula I which isselected from the group consisting of:4-[3-(3,5-di-tert-betyl-4-oxo-2,5-cyclohexadien-1-ylidene)-1-propynyl]benzoicacid, 4-[3-(3,5-di-tert-betyl-4-hydroxyphenyl]-1-propynyl]benzoic acid,2-hydroxy-4-[3-(3,5-di-tert-butyl-4-oxo -2,5-cyclohexadien-1-ylidene)-1-propynyl]benzoic acid, and2-hydroxy-4-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-propynyl]benzoicacid.
 31. The propynyl bioaromatic compound of formula I which thecompound is2-hydroxy-4-[3-(4,4-dimethylthiochroman-6-yl)-1-propynyl]benzoic acid.